WO1993012429A1 - Procede et appareil pour la determination directe des lipoproteines de basse densite - Google Patents

Procede et appareil pour la determination directe des lipoproteines de basse densite Download PDF

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Publication number
WO1993012429A1
WO1993012429A1 PCT/US1992/010809 US9210809W WO9312429A1 WO 1993012429 A1 WO1993012429 A1 WO 1993012429A1 US 9210809 W US9210809 W US 9210809W WO 9312429 A1 WO9312429 A1 WO 9312429A1
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WO
WIPO (PCT)
Prior art keywords
ldl
low density
group
process according
density lipoprotein
Prior art date
Application number
PCT/US1992/010809
Other languages
English (en)
Inventor
Wai Tak Law
Gerhard Ertingshausen
Original Assignee
Actimed Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actimed Laboratories, Inc. filed Critical Actimed Laboratories, Inc.
Priority to EP93901285A priority Critical patent/EP0619885B1/fr
Priority to JP5511132A priority patent/JPH07501945A/ja
Priority to DE69214297T priority patent/DE69214297D1/de
Priority to AU32796/93A priority patent/AU661097B2/en
Publication of WO1993012429A1 publication Critical patent/WO1993012429A1/fr
Priority to FI942763A priority patent/FI942763A/fi
Priority to NO942197A priority patent/NO942197D0/no

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/044—Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y10T436/104165—Lipid, cholesterol, or triglyceride standard or control
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/25875—Gaseous sample or with change of physical state

Definitions

  • the present invention relates to a process for the direct determination of low density lipoprotein in body fluids. More specifically, the present invention relates to a process and apparatus for determination of low density lipoprotein by selectively precipitating low density lipoprotein from a sample, providing enzymes which selectively consume the high density lipoprotein, and then resolubilizing the low density fraction and determining this fraction enzymatically.
  • Lipoproteins are complex particles consisting of protein and lipid which are found in the circulatory system.
  • One of the functions of lipoproteins is to carry water-insoluble substances such as cholesterol and cholesterol esters for eventual cellular use. While all cells require cholesterol for growth, excess accumulation of cholesterol by cells is known to lead to certain diseases, including atherosclerosis.
  • LDL When LDL is precipitated with polyanions such as dextran sulfate and divalent cations such as magnesium, the precipitate redissolves if one tries to selectively convert the cholesterol in the supernatant by an enzymatic assay which requires the presence of surfactants. Moreover, cholesterol esterase and cholesterol oxidase present in the system hydrolyze the LDL.
  • LDL is estimated by the total cholesterol, HDL, and triglyceride contents of the sample.
  • This method requires multiple assays, and is not accurate for samples containing high levels of triglycerides. Consequently, there is a need for a simpl procedure or device for the determination of LD lipoprotein accurately.
  • LDL precipitate normally dissolves quickly in the presence of surfactants such as sodium cholate, and cholesterol esterase usually rapidly hydrolyzes any cholesterol esters in lipoproteins in the presence of suitable surfactants.
  • surfactants such as sodium cholate
  • cholesterol esterase usually rapidly hydrolyzes any cholesterol esters in lipoproteins in the presence of suitable surfactants.
  • the presence of sufficient small particles to provide nucleating agents for clusters of LDL stabilizes the clusters against the effect both of surfactants and of cholesterol esterase.
  • the VLDL can be precipitated first, and then the LDL is precipitated with the specific precipitating reagents and nucleating particles of the present invention.
  • Enzymes are added to react with HDL in the sample, and the LDL is redissolved and detected according to conventional detection means for LDL. Enzymatic means for detecting LDL are preferred.
  • the nucleating particles preferably range in size from about 0.1 to about 100 microns, and may be either mixed with the polyanionic compound or the polyanionic compound may be immobilized thereon.
  • the preferred particles are porous iron oxide.
  • Figure 1 is a side view of a direct LDL measurement device according to the present invention.
  • Figure 2 is a side view of another direct LDL measurement device according to the present invention.
  • a fluid sample such as whole blood
  • a precipitating reagent preferably comprises a mixture of large polyanions and divalent cations, and the precipitation reaction is mediated by nucleating particles.
  • the clusters of LDL so formed are surprisingly stable in the presence of cholesterol enzymes. Cholesterol enzymes, such as cholesterol oxidase and cholesterol esterase, are then added to the sample. At this point the HDL and VLDL lipoproteins in the liquid phase are consumed, while the solid phase LDL clusters remain intact.
  • the LDL is then redissolved by a redissolution agent, and is then analyzed by any conventional means.
  • the polyanions that can be used for forming the LDL clusters can be any polyanions which precipitate lipoproteins which do not interfere with subsequent assays for LDL.
  • the polyanions that can be used are dextran sulfate, heparin, phosphotungstic acid, and polyvinyl sulfate.
  • the dextran sulfate can be high molecular (i.e., molecular weight of from 5 x 10 4 to 2 x 10 6 ) or short-chained (molecular weight of from 5000 to 50,000) .
  • the preferred concentration ranges of the polyanions in the reaction mixture are from about 0.1 to about 8 grams/liter in the case of high molecular weight dextran sulfate, from about l to about 15 grams/liter in the case of short-chained dextran sulfate and heparin, from about 0.2 to about 5 grams/liter in the case of polyvinyl sulfate, and from about 0.3 to about 6 grams/liter in the case of phosphotungstic acid.
  • the LDL determination can, for example, take place by saponification with alcoholic potassium hydroxide solution and chemical determination according to Liebermann- Burchard. However, it is preferred to use an enzymatic determination using cholesterol oxidase (CO) and a cholesterol ester-splitting enzyme or enzyme system, such as cholesterol esterase (CE) . In the case of the use of cholesterol oxidase, the determinations can be based upon the amount of oxygen consumed, the amount of cholest-4- one-3-one formed, or the amount of hydrogen peroxide formed using conventional methods for this purpose. Since the determination of bound cholesterol is well known, there is no need to describe it it detail. The invention is not limited to any method of determining a precipitated LDL.
  • the particles that can be used as nucleating agents for forming the LDL clusters can be any nucleating particles that do not interfere with the subsequent assay for LDL.
  • iron oxide, chromium dioxide, stainless steel, silicon dioxide, glass, methyl methacrylate particles, and the like can all be used.
  • These nucleating agents must be insoluble in the liquids used in the assay, i.e., generally insoluble in water.
  • the particle may be organic or inorganic, and, if inorganic, may be amorphous or crystalline.
  • the inorganic salts may be, but are not limited to, metal salts, such as salts of iron or chromium.
  • inorganic salts metal or otherwise, oxide (including dioxide) salts are preferred, as they are unlikely to interfere with an oxidative reaction.
  • the particle size is preferably between about 0.5 and 200 microns, more preferably 1-10 microns.
  • porous iron oxide with an average diameter of from about 1 to about 10 microns (Reference Diagnostics, Arlington, Mass.), is most preferred.
  • the nucleating agent precipitates more than 50%, more preferably, at least 75%, still more preferably at least 95% of the LDL.
  • substantial precipitation occurs in less than 120 seconds, more preferably less than 60 seconds, still more preferably less than 30 seconds. It is desirable that a good solid pellet be formed and that the pellet be readily redisolved by the redissolving agent.
  • the nucleating agent stabilizes the precipitate so that less than 20%, more preferably less than 10%, is redissolved by cholesterol esterase and/or cholesterol oxidase.
  • the redissolution agent for redissolving the LDL that was found to be most effective was a mixture of EDTA and sodium chloride, however, the invention is not limited to this agent.
  • Other chaotropic agents and/or surfactants known in the art may be used. When a combination of EDTA and sodium chloride is used, a solution of 2.5 - 6.5% sodium chloride and 0.05 - 0.10% EDTA is especially preferred.
  • Other redissolution agents such as from about 75-100 units protease per test and from 50 to 200 mM magnesium chloride per test can also be used.
  • the redissolution agents change the ionic strength of the sample, breaking up the lipoprotein clusters in less than thirty seconds.
  • the redissolution agent may be provided in a liquid or solid (but solubilizable) phase.
  • the particle enhanced LDL precipitate 22 does not dissolve and does not react with the cholesterol enzymes, so that only the HDL and the VLDL react with the cholesterol enzymes, and the hydrogen peroxide generated thereby is consumed by endogenous catalase in less than ten minutes.
  • Zone 14 is a thin sucrose coating and is designed to dissolve in less than ten minutes.
  • An alternative dissolvable coating may also be used.
  • An LDL redissolution zone, zone 15, contains dried hydroxylamine (HA) , or an alternative catalase inhibitor, and LDL redissolution agents.
  • HA dried hydroxylamine
  • zone 14 is dissolved, both the hydroxylamine and the LDL redissolution agents are mixed with the contents of the LDL precipitating zone 13, where the catalase is inhibited by hydroxylamine and the LDL clusters are then dissolved by the action of the LDL redissolution agents.
  • the re-dissolved LDL then reacts with cholesterol oxidase and cholesterol esterase, or other agents which catalyze hydrogen peroxide- generating reactions when LDL is available as a substrate, generating hydrogen peroxide which flows through a timing barrier 17 into the measurement zone 16 on the device.
  • the length of the color bar developed in the measurement zone is proportional to the concentration of the LDL in the whole blood sample.
  • the reactions in zone 13 are as follows:
  • the LDL ppt is not oxidized by air, despite the presence of CO and CE.
  • the hydroxylamine inhibits catalase-mediated enzymolysis of the H 2 0 2 .
  • the device of the present invention can be used with a different enzyme system, as shown in Figure 2.
  • whole blood is introduced into the device 10 at 20, the top of layer 11. Red blood cells are trapped in zone 11, and plasma enters zone 13.
  • a particle enhanced LDL precipitation reagent 38 in zone 13 causes LDL to precipitate in large clusters 22 in less than 60 seconds.
  • zone 13 is buffered to about pH 9, and contains cholesterol esterase, cholesterol oxidase, cholesterol dehydrogenase (CDH) , redissolution agents, NAD, surfactants and cation exchange resins.
  • HDL in the plasma reacts with cholesterol esterase, cholesterol dehydrogenase and NAPD to produce NAPDH, while the LDL precipitate remains unaffected.
  • the pH in zone 13 drops with time because of the cation exchange resins which was placed inside this zone. Additionally, as the pH falls from 9.0 to 7.0, the cholesterol dehydrogenase becomes inactivated, while the cholesterol oxidase and protease become activated. The LDL precipitate is then dissolved by the protease, and cholesterol esterase and cholesterol oxidase react with LDL to generate hydrogen peroxide. The hydrogen peroxide so generated flows through the timing barrier 17 into the measurement zone 16. The length of the color bar developed in the measurement zone is proportional to the concentration of the LDL in the whole blood sample.
  • a specific precipitation reagent for an undiluted plasma sample can be optimized by varying the concentration of magnesium chloride in the presence of 10 gram/L dextran sulfate (MW 50,000) . As shown in Table 1, at 75 mM magnesium chloride concentration, only LDL precipitated out of the plasma, while HDL and VLDL remained in the plasma. Table 1 shows the concentration of cholesterol in plasma after precipitation and slow- speed centrifugation.
  • the optimum amount of magnesium chloride for forming a precipitate of LDL ranges from about 75 mM to about 500 mM.
  • the LDL is precipitated preferentially from the VLDL and HDL.
  • the LDL precipitates formed are not stable in the presence of cholesterol enzymes such as cholesterol esterase and cholesterol oxidase, which enzymes are used to consume the HDL and VLDL from the sample so that these latter lipoproteins do not interfere with the LDL assay.
  • Samples of 500 ⁇ L plasma with known assayed values of VLDL, HDL and LDL were treated with an LDL precipitating reagent with and without nucleating agents (40 mg porous iron oxide particles/mL solution) for one minute.
  • the nucleating agent of choice was porous iron oxide, with average diameters ranging from 1 to 10 microns.
  • an enzyme reagent containing 4 mg of sodium cholate and 30 units of cholesterol esterase was added to each sample. After three minutes of incubation, the precipitates were spun down at 3000 RPM and the supernatants were assayed for cholesterol values.
  • the data in Table 2 show that the LDL precipitate formed with the nuclei remained insoluble in the presence of surfactant and cholesterol esterase, unlike clusters formed in Example l in the absence of nucleating particles.
  • the final amount of sodium chloride in the sample is from about 2.5 - 6.5' and the amount of EDTA is from about 0.05 - 0.12%.
  • recovery is at least 90%, more preferably at least 95%.

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Abstract

L'analyse des lipoprotéines de basse densité a lieu directement dans les échantillons de fluide en précipitant de façon sélective les lipoprotéines de basse densité contenues dans l'échantillon par la formation de grappes, en consommant de façon sélective les lipoprotéines de haute densité et de très basse densité et en resolubilisant les lipoprotéines de basse densité en vue de leur détermination directe. On forme les grappes en traitant l'échantillon de fluide avec un mélange contenant un composé polyanionique, un métal bivalent et un agent de nucléisation. Les grappes sont dissoutes à nouveau et analysées.
PCT/US1992/010809 1991-12-13 1992-12-11 Procede et appareil pour la determination directe des lipoproteines de basse densite WO1993012429A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP93901285A EP0619885B1 (fr) 1991-12-13 1992-12-11 Procede et appareil pour la determination directe des lipoproteines de basse densite
JP5511132A JPH07501945A (ja) 1991-12-13 1992-12-11 低密度リポタンパク質の直接的決定方法／装置
DE69214297T DE69214297D1 (de) 1991-12-13 1992-12-11 Verfahren und gerät zur direkten bestimmung von lipoproteinen mit niedriger dichte
AU32796/93A AU661097B2 (en) 1991-12-13 1992-12-11 Process and apparatus for direct determination of low density lipoprotein
FI942763A FI942763A (fi) 1991-12-13 1994-06-10 Menetelmä ja laite pienitiheyksisen lipoproteiinin suoran määrityksen tekemiseksi
NO942197A NO942197D0 (no) 1991-12-13 1994-06-10 Fremgangsmåte og anordning for direkte bestemmelse av LD-lipoprotein

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US806,183 1991-12-13
US07/806,183 US5286626A (en) 1991-12-13 1991-12-13 Process and apparatus for direct determination of low density lipoprotein

Publications (1)

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WO1993012429A1 true WO1993012429A1 (fr) 1993-06-24

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PCT/US1992/010809 WO1993012429A1 (fr) 1991-12-13 1992-12-11 Procede et appareil pour la determination directe des lipoproteines de basse densite

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US (2) US5286626A (fr)
EP (1) EP0619885B1 (fr)
JP (1) JPH07501945A (fr)
AT (1) ATE143732T1 (fr)
AU (1) AU661097B2 (fr)
CA (1) CA2124949A1 (fr)
DE (1) DE69214297D1 (fr)
FI (1) FI942763A (fr)
NO (1) NO942197D0 (fr)
WO (1) WO1993012429A1 (fr)

Cited By (1)

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WO1996041198A1 (fr) * 1995-06-07 1996-12-19 Genzyme Corporation Procede d'isolation de la lipoproteine (a), permettant la determination quantitative ulterieure de sa masse et de sa teneur en cholesterol

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JP2799835B2 (ja) * 1995-01-31 1998-09-21 第一化学薬品株式会社 コレステロールの定量方法
DE19505894A1 (de) * 1995-02-21 1996-08-22 Boehringer Mannheim Gmbh Verfahren und Reagenz zur spezifischen Bestimmung von LDL in Serumproben
JP3256241B2 (ja) * 1995-03-16 2002-02-12 協和メデックス株式会社 低密度リポ蛋白中のコレステロールの定量法
EP0764848A4 (fr) * 1995-03-20 2001-04-11 Kyowa Medex Co Ltd Methode de quantification du cholesterol dans une lipoproteine a faible densite ou a tres faible densite
US5614414A (en) * 1995-03-30 1997-03-25 Streck Laboratories, Inc. Liquid lipoprotein control
US5770451A (en) * 1995-03-30 1998-06-23 Streck Laboratories, Inc. Liquid lipoprotein control
JP3193634B2 (ja) 1996-05-29 2001-07-30 第一化学薬品株式会社 Ｌｄｌコレステロールの定量方法
KR980010429A (ko) * 1996-07-18 1998-04-30 다나까 모또아끼 콜레스테롤 측량용 시약
EP0821239A3 (fr) * 1996-07-25 1998-06-17 Wako Pure Chemical Industries, Ltd Méthode pour la mesure d'une quantité de cholesterol des lipoprotéines à faible densité (LDL)
ES2278395T3 (es) * 1997-04-14 2007-08-01 Denka Seiken Co., Ltd. Procedimiento para cuantificar el colesterol en lipoproteinas de baja densidad.
US5814472A (en) * 1997-05-13 1998-09-29 Wako Pure Chemical Industries, Ltd. Measurement of LDL-cholesterol
US5925534A (en) * 1998-06-08 1999-07-20 Wako Pure Chemical Industries, Ltd. Method for measuring LDL-cholesterol
CN1187609C (zh) 1999-11-22 2005-02-02 松下电器产业株式会社 胆固醇传感器和胆固醇的定量方法
US7087397B2 (en) * 2001-12-21 2006-08-08 Polymer Technology Systems, Inc, Method for determining HDL concentration from whole blood or plasma
DE60207196T2 (de) * 2002-04-09 2006-07-20 Cholestech Corp., Hayward Verfahren und Vorrichtung zur Quantifizierung von Lipoprotein-Cholesterol hoher Dichte
EP1434054A1 (fr) * 2002-12-25 2004-06-30 Matsushita Electric Industrial Co., Ltd. Biocapteur pour la determination de cholesterol des lipoprotéines à faible densité (LDL)
US20050032141A1 (en) * 2003-07-17 2005-02-10 Dimagno Theodore John Dry analytical element for high-density lipoprotein cholesterol quantification
US7435577B2 (en) * 2004-02-03 2008-10-14 Polymer Technology Systems, Inc. Direct measurement of chlolesterol from low density lipoprotein with test strip
US7772007B2 (en) * 2004-04-02 2010-08-10 Cholestech Corporation Assay device for direct measurement of LDL cholesterol
US7491542B2 (en) * 2004-07-12 2009-02-17 Kim Scheuringer Test device for determining the concentration of LDL-cholesterol in a sample
DE602008002825D1 (de) * 2007-01-09 2010-11-11 Cholestech Corp Vorrichtung und verfahren zur messung des ldl-assoziierten cholesterols

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WO1979000306A1 (fr) * 1977-11-21 1979-05-31 Univ Boston Determination du cholesterol des lipoproteines a faible densite (ldl) dans les fluides du corps
EP0013814A1 (fr) * 1978-12-15 1980-08-06 Beckman Instruments, Inc. Méthode de précipitation améliorée de lipoprotéines de densité peu élévée, réactif à cet effet et comprimé contenant ce réactif
EP0035211A1 (fr) * 1980-02-29 1981-09-09 Roche Diagnostics GmbH Procédé et réactif pour la détermination de bêta-lipoprotéines (L.D.L.)
EP0174478A2 (fr) * 1981-09-10 1986-03-19 B. Braun Holding AG Procédé pour la précipitation sélective extracorporelle des lipoprotéines à basse densité dans du sérum ou du plasma sanguin
EP0428980A1 (fr) * 1989-11-17 1991-05-29 Abbott Laboratories Détermination de HDL dans le sang total

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Publication number Priority date Publication date Assignee Title
US5783400A (en) * 1990-04-27 1998-07-21 Genzyme Corporation Method for the isolation of lipoprotein allowing for the subsequent quantification of its mass and cholesterol content
WO1996041198A1 (fr) * 1995-06-07 1996-12-19 Genzyme Corporation Procede d'isolation de la lipoproteine (a), permettant la determination quantitative ulterieure de sa masse et de sa teneur en cholesterol

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FI942763A0 (fi) 1994-06-10
FI942763A (fi) 1994-06-10
AU661097B2 (en) 1995-07-13
AU3279693A (en) 1993-07-19
US5286626A (en) 1994-02-15
JPH07501945A (ja) 1995-03-02
ATE143732T1 (de) 1996-10-15
US5411870A (en) 1995-05-02
EP0619885B1 (fr) 1996-10-02
NO942197L (fr) 1994-06-10
NO942197D0 (no) 1994-06-10
DE69214297D1 (de) 1996-11-07
CA2124949A1 (fr) 1993-06-24
EP0619885A1 (fr) 1994-10-19

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